Healthy young persons incapacitated for response to the vaccine for hepatitis B virus (nonresponders) fail to make detectable antibody to the major virus envelope protein, HbsAg, and comprise 4% of subjects. Previous work has shown nonresponse to be associated with a lack of HbsAg-specific T cell proliferation, to be recessively inherited, to be MHC-linked and associated with specific extended MHC haplotypes. From mixing experiments, it is clear that the defect in nonresponders in their T cells, not in their antigen presenting cells. We hypothesize that nonresponse is part of a continuum from total nonresponse to both a strong humoral and cellular immune response and that nonresponse is not due to a hole in the T cell repertoire. Additionally, evidence that the class I-restricted CD8+ T cell compartment is or might be functional in response to HB vaccine is extensive. Accordingly, the specific aims of this proposal are: (1) To determine whether the class I-restricted cytotoxic T cell (CTL) compartment is functional in the HbsAg-specific cellular response but defective in nonresponse; (2) To determine whether the relative Th1/Th2 response profile reflects different subclasses of response; (3) To determine whether HbsAg response can be detected soon after the first injection of antigen; and (4) To attempt to predict response and nonresponse in vitro using T cells from subjects naive to HbsAg using dendritic cells for presentation. These experiments should meet our overall objective of understanding the molecular and cellular bases of the human response and nonresponse of HbsAg as a model for the human immune response to vaccination in general.